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L0301P29 - Introduction to Cancer
Cancer *the disease of a single cell **i.e. mutation in one cell causes a change leading to rapid uncontrolled growth *growing mass of cancer cells = tumour *tumour formation caused by errors in signalling the end of cell division Cell Cycle Entry *normal cell growth **cells divide when new cells required **occurs slowly with tight control in order to maintain cell tissue number **cells stop dividing when need is met *tightly regulated cell cycle **i.e. DNA replication and cell division *cells normally respond to chemical signals and enter the cell cycle when instructed *cell divisions are not continuous **controlled by: ***external stimuli ***nutrient availability *extracellular signals = intracellular biochemical response: **cell cycle entry or **arrest in a G1/G0 phase **i.e. either growth promoting or inhibiting Signalling and Regulation Generic Signal Transduction *mutations can occur at any of the steps, including: **in the receptors **in intracellular signalling proteins **in the proteins which deactivate the signal once the response has been created *leading to aberrant signalling pathways Growth Factors (GFs) *over 200 types identified in the body *are not present all the time *circulate in the blood *stimulates cells to divide or differentiate *has multiple effects **regulation of cell cycle progression **cell survival, migration or death *can regulate the cell cycle **stimulate progression of normal and cancer cells from quiescent (dormant) non-dividing state, G0, through to G1 *can regulate cell death **presence of factors inhibit apoptosis **whilst withdrawal of factors over longterm will lead to apoptosis *balance of growth factors and their receptors is needed otherwise it will affect cell growth and proliferation GFs in Clinical Medicine *in the body, a combination of GFs are used; in clinical practice, only single GFs are used *examples include: **platelet derived growth factor **epidermal growth factor **erythropoietin (EPO) ***treatment of anaemia of renal disease ***stimulates the proliferation and differentiation of red cells **granulocyte macrophage colony-stimulating factor (GM-CSF) ***stimulates blood stem cell proliferation and mobilisation ***often used after bone marrow transplantation and chemotherapy to aid bone marrow recovery  GFs Role in Cancer *GFs or their receptors can be mutated causing them to be overactive or inappropriately active *constitutive (permanent) activation of receptors can occur leading to cancer *example: **epidermal growth factor receptor II = breast cancer prognostic marker **tumours produce GFs such asIGF-1, IGF-2, EGF which stimulate tumour growth in an autocrine fashion *mechanisms that lead to GF overproduction in tumours is not clear Normal Cell Proliferation Regulation By exiting and entering the cell cycle Normal cells: *may respond to external signals to enter G0 *may be stimulated to return to the cell cycle at G1 by environmental cues *undergo limited number of divisions before they stop proliferating **thus cells slow down or halt cell proliferation as a person ages **controlled by telomere shortening: become so short that DNA is at risk of being damaged and cell is signalled to undergo apoptosis Cancer cells: *ignore signals to enter G0 and continue proliferating   By post-mitotic differentiation Normal cells: *permanently leave cell cycle by differentiating into a specialised cell type *some are rapidly and constantly renewed from stem cells include: skin, bone marrow, lining of the intestine *stem cells **no limit on capability to renew themselves **inducing them to enter post mitotic differentiation will decrease a tissue’s pool of replicating cells *when a normal stem cell divides results in: **one daughter cell which remains a stem cell to maintain the stem cell pool **the other daughter cell will go on a course leading to irreversible terminal differentiation (i.e. reach its final specialised form) Cancer cells: *fail to undergo terminal differentiation *cannot carry out function of the normal healthy tissue and crowds out healthy cells *continue proliferating to form a tumour By programmed cell death *some cells programmed to self-destruct by apoptosis *eliminates healthy cells during development and eliminates damaged cells that can pose a threat to the organism *mutations that compromise a cell’s ability to carry out apoptosis can result in tumour formation *some cancer cells can inactivate apoptotic mechanisms and cannot be destroyed  Cancer Progression *cancers progress from: **a single mutant cell ***mutation in growth regulatory gene **to a tumour **then to metastasis *is a multistep process that requires at least four to six different mutations to reach the tumour state *can take decades for a single mutant cell to proliferate into a palpable tumour Tumours *single cell sustains mutation in one of its growth-regulating genes causing it to proliferates more rapidly *all the clones of the parent cell **will also contain the mutation **have a higher chance of acquiring a mutation themselves due to uncontrolled cell growth (no DNA repair) **increase in mutations = tumour grows *tumorigenesis progresses by clonal expansion *increasingly abnormal cells outgrow their less mutant neighbours   Cancer Cells *difficult to study in vivo, and thus have been created in vitro Distinct Properties *do not stop dividing when they contact a neighbouring cell **contact inhibition occurs in normal cells **cancer cells do not require attachment to a physical substate in order to grow *have a greatly reduced requirement for growth factors to sustain proliferation *are resistant to growth-inhibitory signals *unlike normal cells in culture, which plateau/halt division after a certain number of growth-and-division cycles, cancer cells: **are immortal ***do not plateau after infinite days ***re-express telomerase to extend telomeres for continuous replication **do not stop dividing after a predetermined number of generations **often have chromosomal aberrations ***including changes in chromosome number and structure Tissue Mass *balance between cell division and cell death Normal: *in normal tissues, cells may proliferate continually but numbers remain steady because cell production is balanced by cell loss (apoptosis) *if too many cells are produced, the rate of apoptosis will increase to dispose of the surplus Cancer: *deregulated cell growth is the defining feature of all cancers *cancer cells fail to commit suicide when a normal cell would do so *great increase in organ size **normal cells have been crowded out **can lead to failure of the organ and death of the patient 